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Genetic and Pathological Characteristics of Frontotemporal Dementia with Right Anterior Temporal Predominance: A Multicenter Retrospective Cohort Study

Ulugut, Hulya ; Younes, Kyan ; Bertoux, Maxime ; Montembeault, Maxime ; Fumagalli, Giorgio G. ; Ghirelli, Alma ; Spinelli, Edoardo G. ; Jung, Na Yeon ; Samancı, Bedia and Illán-Gala, Ignacio , et al. (2025) In Alzheimer's & dementia : the journal of the Alzheimer's Association 21.
Abstract

BACKGROUND: Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. METHODS: Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. RESULTS: Genetic screening was performed... (More)

BACKGROUND: Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. METHODS: Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. RESULTS: Genetic screening was performed on 51% (n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA-binding protein 43 type C (TDP-C) pathology was most prevalent (60%, n = 32), while tau-MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP-C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP-C cases. However, left handedness was more common in TDP-C cases (14%) compared to genetic cases (5%). CONCLUSION: While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

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Alzheimer's & dementia : the journal of the Alzheimer's Association
volume
21
article number
e103987
publisher
Wiley
external identifiers
  • pmid:41447622
  • scopus:105025872107
ISSN
1552-5279
DOI
10.1002/alz70857_103987
language
English
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yes
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Publisher Copyright: © 2025 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
id
13fdae15-ef64-42f3-a2ab-a328e8d9811d
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2026-01-05 08:24:27
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@article{13fdae15-ef64-42f3-a2ab-a328e8d9811d,
  abstract     = {{<p>BACKGROUND: Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&amp;D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. METHODS: Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. RESULTS: Genetic screening was performed on 51% (n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA-binding protein 43 type C (TDP-C) pathology was most prevalent (60%, n = 32), while tau-MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP-C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP-C cases. However, left handedness was more common in TDP-C cases (14%) compared to genetic cases (5%). CONCLUSION: While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.</p>}},
  author       = {{Ulugut, Hulya and Younes, Kyan and Bertoux, Maxime and Montembeault, Maxime and Fumagalli, Giorgio G. and Ghirelli, Alma and Spinelli, Edoardo G. and Jung, Na Yeon and Samancı, Bedia and Illán-Gala, Ignacio and Thompson, Jennifer and Kobylecki, Christopher and Santillo, Alexander and Englund, Elisabet and Waldö, María Landqvist and Riedl, Lina and Van den Stock, Jan and Vandenbulcke, Mathieu and Vandenberghe, Rik and Laforce, Robert and Ducharme, Simon and Pressman, Peter S. and Tartaglia, Carmela and Caramelli, Paulo and de Souza, Leonardo Cruz and Takada, Leonel Tadao and Morin, Alexandre and Schroeter, Matthias L. and Kim, Eun Joo and Moon, So Young and Agosta, Federica and Canu, Elisa and Filippi, Massimo and Gurvit, Hakan and Diehl-Schmid, Janine and Galimberti, Daniela and Lebouvier, Thibaud and Miller, Bruce L. and Sturm, Virginia E. and Miyagawa, Toji and Whitwell, Jennifer L. and Boeve, Brad F. and Rohrer, Jonathan D. and Tempini, Maria Luisa Gorno and Josephs, Keith A. and Snowden, Julie S. and Warren, Jason D. and Rankin, Katherine P. and Pijnenburg, Yolande A.L.}},
  issn         = {{1552-5279}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & dementia : the journal of the Alzheimer's Association}},
  title        = {{Genetic and Pathological Characteristics of Frontotemporal Dementia with Right Anterior Temporal Predominance: A Multicenter Retrospective Cohort Study}},
  url          = {{http://dx.doi.org/10.1002/alz70857_103987}},
  doi          = {{10.1002/alz70857_103987}},
  volume       = {{21}},
  year         = {{2025}},
}